Controlled-release apoptosis modulating compositions and methods for the treatment of otic disorders

Abstract

Disclosed herein are compositions and methods for the treatment of otic disorders with anti-apoptotic agent or pro-apoptotic agent compositions and compositions administered locally to an individual afflicted with an otic disorder, through direct application of these compositions and compositions onto or via perfusion into the targeted auris structure(s).

1 - 19 . (canceled) 
     
     
         20 . A method of preventing drug-induced ototoxicity in an individual in need thereof comprising intratympanic administration of a pharmaceutical composition comprising an anti-apoptotic agent, or a pharmaceutically acceptable salt thereof, to the individual in need thereof prior to onset of therapy with the drug. 
     
     
         21 . The method of  claim 20 , wherein the pharmaceutical composition comprises an auris acceptable carrier. 
     
     
         22 . The method of  claim 21 , wherein the auris acceptable carrier comprises an auris acceptable gel. 
     
     
         23 . The method of  claim 22 , wherein the auris acceptable gel is a thermoreversible gel. 
     
     
         24 . The method of  claim 23 , wherein the auris acceptable gel comprises a polyoxyethylene-polyoxypropylene triblock copolymer. 
     
     
         25 . The method of  claim 23 , wherein the auris acceptable gel comprises a poloxamer. 
     
     
         26 . The method of  claim 25 , wherein the auris acceptable gel comprises Poloxamer 407. 
     
     
         27 . The method of  claim 25 , wherein the pharmaceutical composition comprises between about 14% and about 21% of the poloxamer. 
     
     
         28 . The method of  claim 27 , wherein the pharmaceutical composition comprises between about 15% and about 18% of the poloxamer. 
     
     
         29 . The method of  claim 28 , wherein the pharmaceutical composition comprises about 16% of the poloxamer. 
     
     
         30 . The method of  claim 22 , wherein the auris acceptable gel provides a gelation temperature of between about 19° C. to about 42° C. 
     
     
         31 . The method of  claim 20 , wherein the anti-apoptotic agent is an inhibitor of c-Jun N-terminal kinase (JNK). 
     
     
         32 . The method of  claim 31 , wherein the inhibitor of JNK is selected from the group consisting of D-JNKI-1 ((D)-hJIP 175-157 -DPro-DPro-(D)-HIV-TAT 57-48 ), AM-111 (Auris), SP600125 (anthra[1,9-cd]pyrazol-6(2H)-one), JNK Inhibitor I ((L)-HIV-TAT 48-57 -PP-JBD 20 ), JNK Inhibitor III ((L)-HIV-TAT 47-57 -gaba-c-Junδ 33-57 ), AS601245 (1,3-benzothiazol-2-yl (2-[[2-(3-pyridinyl) ethyl]amino]-4 pyrimidinyl)acetonitrile), JNK Inhibitor VI (H 2 N-RPKRPTTLNLF-NH 2 ), JNK Inhibitor VIII (N-(4-Amino-5-cyano-6-ethoxypyridin-2-yl)-2-(2,5-dimethoxyphenyl)acetamide), JNK Inhibitor IX (N-(3-Cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)-1-naphthamide), dicumarol (3,3′-Methylenebis(4-hydroxycoumarin)), SC-236 (4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yllbenzene-sulfonamide), CEP-1347 (Cephalon), CEP-11004 (Cephalon); and a combination thereof. 
     
     
         33 . The method of  claim 32 , wherein the inhibitor of JNK is SP600125. 
     
     
         34 . The method of  claim 20 , wherein the drug-induced ototoxicity is hearing loss. 
     
     
         35 . The method of  claim 20 , wherein the drug-induced ototoxicity is chemotherapy-induced ototoxicity. 
     
     
         36 . The method of  claim 35 , wherein the chemotherapeutic agent that induces ototoxicity is selected from the group consisting of actinomycin, bleomycin, cisplatin, carboplatin and vincristine. 
     
     
         37 . The method of  claim 36 , wherein the chemotherapeutic agent is cisplatin. 
     
     
         38 . The method of  claim 20 , wherein the pharmaceutical composition provides sustained release of the anti-apoptotic agent into the ear for a period of at least 5 days after a single administration.